One step preparation of poly(amide-anhydride)

ABSTRACT

A method for synthetizing polyanhydrides in solution using coupling agents and a removable acid acceptor to effect a one-step polymerization of dicarboxylic acids. As used in the method, these coupling agents include phosgene, diphosgene, and acid chlorides. Insoluble acid acceptors include insoluble polyamines and crosslinked polyamines such as polyethyleneimine and polyvinylpyridine and inorganic bases such as K 2  CO 3 , Na 2  CO 3 , NaHCO 3 , and CaCO 3 . The only byproduct formed is a removable hydrochloric acid-acid acceptor. 
     Examples are provided of the polymerization of highly pure polyanhydrides using phosgene, diphosgene or an acid chloride as the coupling agent, in combination with either an insoluble acid acceptor or a soluble acid acceptor in a solvent wherein the polymerizaiton byproduct or polymer is insoluble. 
     A particularly important application of these polyanhydrides is in the formation of drug delivery devices containing bioactive compounds. The method is also useful in the polymerization of dicarboxylic acids including heat liable dipeptides of glutamic or aspartic acid.

This is a divisional of U.S. Ser. No. 080,332 entitled "One-StepPolymerization of Polyanhydrides" filed July 31, 1987 by Abraham J.Domb, Robert S. Langer, Eyal Ron, Steven Giannos, Rohit Kothari andEdith Mathiowitz.

BACKGROUND OF THE INVENTION

This invention is generally in the area of polyanhydride synthesis andis in particular a method and reagents for polymerizing extremely purepolyanhydrides using solution polymerization.

Polyanhydrides are particularly useful for biomedical applications,especially in drug delivery devices, since they are biodegradable,undergo surface erosion and have erosion rates that can be changedseveral thousandfold by simple changes in the choice of the monomers.However, the methods for preparing highly pure polyanhydrides frequentlyrequire a number of processing steps, involve compounds which can leavetoxic residues in the polyanhydride to be used in making the drugdelivery device, and yield low molecular weight polymers due tohydrolysis of the anhydride bonds during purification.

At the present time, polyanhydrides are most commonly prepared by meltpolycondensation. In this method, dicarboxylic acid monomers (thediacids) are first converted to the mixed anhydride with acetic acid andthen polymerized under vacuum at elevated temperatures to yield thepolyhydrides. In the preferred method, the temperature is limited and adry ice trap is used to maximize the molecular weight of the finalproduct. Purer polymers are obtained using highly purified diacids andprepolymers. Unfortunately, due to the high temperatures, this method islimited to heat-stable monomers.

A second method for polymerizing polyanhydrides is solutionpolymerization. Solution polymerization appears to be the method ofchoice for heat sensitive monomers. A variety of solutionpolymerizations of polyanhydrides at ambient temperatures have beenreported, fpr example, by Yoda, et al., Bull. Chem. Soc. Japan 32, 1120(1959) and Subramanyam, et al. Macromol. Sci. Chem. 822 (1), 23 (1985).Since the formation of an anhydride is essentially a dehydrativecoupling of two carboxyl groups, it can be effected at room temperatureby a dehydrochlorination between a diacid and a dicarboxylic acid in thepresence of a base to yield the polyanhydride and the base.HCl, areaction known as a Schotten-Bauman condensation. Polymerization at lowtemperatures in solution is also possible using a powerful dehydrativecoupling reagent.

As described by Leong, et al., in Macromolecules 20(4), 705 (1987), thismethod also has a number of limitations. Leong et al examinedmelt-polycondensation, dehydrochlorination, and dehydrative coupling,focusing on the use of organophosphorus catalysts in the latter. Henoted a number of specific disadvantages to the methods. The molecularweight of the polymer which is produced is frequently low, for example,polyterephthalic anhydride synthesized by dehydrative coupling has amolecular weight of only about 2100. Further, there are problems withthe isolation and hydrolysis of the final product. Partial hydrolysis ofthe diacid chloride in the presence of pyridine as an acid acceptor isone cause of low molecular weight polymers. The dehydration couplingagents may also detrimentally affect polyanhydride formation, asreported for N,N-Bis(2-oxo-3-oxazolidinylphosphinic chloride, phenylN-phenylphosphoramidochloridate, dicyclohexylcarbodiimide, andchlorosulfonyl isocyanate, which yielded impure polymers of lowmolecular weight. Further, the final products contain polymerizationbyproducts such as amine-hydrochloride and dehydrative agent residueswhich have to be removed by washing with protic solvents. The washingstep may cause hydrolysis of the polymer.

It is therefore an object of the present invention to provide a methodfor polymerization of heat sensitive monomers including dipeptides andtherapeutically active diacids.

It is another object of the present invention to provide coupling agentsfor use in solution polymerizations of polyanhydrides.

It is a further object of the present invention to provide a methodusing the coupling agents to provide a single-step polymerization methodfor polyanhydrides, not requiring additional steps for the removal ofbyproducts.

SUMMARY OF THE INVENTION

A method for synthesizing polyanhydrides in solution using couplingagents and a removable acid acceptor to effect a one-step polymerizationof dicarboxylic acids. As used in the method, these coupling agentsinclude phosgene, diphosgene, and acid chlorides. Insoluble acidacceptors include insoluble polyamines and crosslinked polyamines suchas polyethyleneimine and polyvinylpyridine and inorganic bases such asK₂ CO₃, Na₂ CO₃, NaHCO₃, and CaCO₃. The only byproduct formed is aremovable hydrochloric acid-acid acceptor.

Examples are provided of the polymerization of highly purepolyanhydrides using phosgene, diphosgene or an acid chloride as thecoupling agent, in combination with either an insoluble acid acceptor ora soluble acid acceptor in a solvent wherein the polymerizationbyproduct or polymer is insoluble.

A particularly important application of these polyanhydrides is in theformation of drug delivery devices containing bioactive compounds. Themethod is also useful in the polymerization of dicarboxylic acidsincluding heat labile dipeptides of glutamic or aspartic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is the reaction of dicarboxylic acids, a coupling agent,phosgene, and an insoluble acid acceptor, crosslinked polyvinylpyridine;

FIG. 1B is the reaction of dicarboxylic acids, a coupling agent,phosgene, and a removable acid acceptor, triethyleneamine, where eitherthe polyanhydride product or the hydrochloric acid-acid acceptor salt isinsoluble in the solvent, depending on the selection of the solvent;

FIG. 1C is the proposed mechanism for the polymerization ofpolyanhydrides using diphosgene as the coupling agent in the presence ofan acid acceptor.

FIG. 2 is the formation of polyanhydrides from dipeptides containingglutamic or aspartic acid which are polymerized using a coupling agentand a removable acid acceptor.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a one-step solution polymerization ofdicarboxylic acids using a coupling agent and a removable acid acceptorto yield extremely pure polyanhydrides. There are essentially twoembodiments of the invention: the first, using an insoluble acidacceptor, and the second, using a solvent system wherein thesolubilities of the polyanhydride and the acid acceptor by-product areso different that one is easily separated from the other.

Coupling agents include dehydrative agents such as phosgene anddiphosgene and acid chlorides such as sebacoyl chloride. Phosgene anddiphosgene are preferred over the acid chlorides since they are notincorporated into the resulting polymer. The advantage is that thecoupling agent can be used to form a variety of polymers, not just apolymer containing the acid residue from the acid chloride.

In the preferred embodiment, the acid acceptor is insoluble in thereaction solution. Examples of useful insoluble acid acceptors includeinsoluble polyamines and crosslinked polyamines such aspolyethyleneimine and poly(4-vinylpyridine) and inorganic bases such asK₂ CO₃, Na₂ CO₃, NaHCO₃, and CaCO₃. The latter react in solution withthe acid to yield the salt, which is insoluble in organic solution, andCO₂.

The reactions of the diacids with the coupling agent in the presence ofa removable acid acceptor, where the acid acceptor is insoluble (e.g., acrosslinked polyamine or inorganic base) is shown in FIG. 1A. Thereaction using a solvent which dissolves either the polyanhydrideproduct or the hydrochloric acid-acid acceptor salt is shown in FIG. 1B.The suggested polymerization mechanism using diphosgene as the couplingagent is shown in FIG. 1C.

Using either embodiment, where the polyanhydride in soluble and thecorresponding acid acceptor-acid is insoluble or where the polymer isinsoluble and the corresponding acid acceptor-acid is soluble, allowsone to purify the product using a single filtration step.

Dichloroformate (phosgene) is a common reagent in organic synthesis andavailable commercially from suppliers such as Morton Thiokol.Trichloromethyl chloroformate (diphosgene) is a considerably less toxicphosgene dimer which is also commercially available. Other advantagesinclude the characteristic that it is a liquid with low vapor pressureat room temperature, not requiring elaborate traps, and can be weigheddirectly It has been used in a number of organic syntheses. For example,alcohols react with diphosgene to yield the correspondingtrichloromethyl carbonate or, in the presence of pyridine, thechloroformate. Further reaction of the trichloromethyl carbonate withalcohol or amine produces the expected carbonate carbamate or carbonate.Isocyanates, ureas and isocyanides are prepared with either diphosgeneor phosgene N-carboxy-alpha-amino acid anhydrides can be prepared fromalpha amino acids using diphosgene. Diphosgene reacts with amino acidsto form isocyanato acid chlorides without the need for additionalreagents such as HCl, as are required in the analagous reaction withphosgene. Diphosgene has also been used to prepare phosphinedichlorides.

Despite the variety of methods these reagents have utility with, theonly polyanhydrides synthesized using phosgene were low molecular weightsebacic acid oligomers, not useful for medical applications In additionto the fact that high molecular weight polyanhydrides have not beenproduced using phosgene, it was not apparent until actually tested thatdiphosgene could be used as a coupling agent since all of the reportedreactions occurred at much higher temperatures (approximately 60° C.),in contrast to the lower temperatures desired in the present method toprevent loss of bioactivity of heat sensitive compounds. Diphosgene isnot as active as phosgene and there was concern that the reaction wouldnot continue on to form the second molecule, shown in FIG. 1C. Thesimpler reaction with phosgene is shown in FIG. 1A and FIG. 1B.

The following nonlimiting examples further describe the presentinvention.

Compounds that were used are: phosgene gas (Matheson, MA), diphosgene(Martin Thiokol, MA), crosslinked poly(4-vinylpyridine) (PVP), sebacicacid (SA), sebacoyl chloride, adipic acid (AA), dodecanedioic acid (DD),terephthalic acid (TPA), 1,4 phenylenedipropionic acid (PDP),triethylamine (TEA), pyridine, tetramethylethylenediamine (TMEDA) (allfrom Aldrich Fine Chemicals, Milwaukee, Wis.). The amine bases weredried over KOH and freshly distilled prior to use. The followingsolvents were used: dioxane, toluene, N,N'dimethylformamide (DMF),dimethylsulfoxide (DMSO), and toluene (gold label, Aldrich, FineChemical, Milwaukee, Wis.). Chloroform and hexanes (petroleum ether)were dried over activated alumina (ICN Biomedical, Eschwege, WestGermany) and distilled before use. All experiments were performed underanhydrous condition.

1,3-bis(p-carboxyphenoxy)propane was synthesized according to Conix, A.,J. Polymer Sci 29, 343 (1958), followed by extraction with ether priorto use. Phosgene solution was prepared by bubbling phosgene gas intotoluene and adjusting the concentration to 1.0M by dilution. Theconcentration of this solution was determined by titration with astandard solution of 0.1N NaOH.

Infrared spectroscopy was performed on a Perkin-Elmer 1430spectrophotometer (Perkin-Elmer, MA). Polymeric samples were film castonto NaCl plates from a solution of the polymer in chloroform.Prepolymer samples were either pressed into KBr pellets or dispersed innujol onto NaCl plates. The melting points of prepolymers weredetermined on a Fisher Johns melting point apparatus. The molecularweight of the polymers was estimated on a Perkin-Elmer GPC system(Perkin-Elmer, MA) consisting of the Series 10 pump and the 3600 DataStation with the LKB 214 - rapid spectral detector at 254 nm wavelength.Samples were eluted in chloroform through two PL Gel columns (PolymerLaboratories; 100 A and 1000 A pore sizes) in series at a flow rate of1.5 ml/min. Molecular weights of polymers were determined relative topolystyrene standards (Polysciences, PA., molecular weight ranges, 500to 1,500,000) using CHROM 2 and GPC 4 computer programs (Perkin-Elmer,MA). Elemental analysis were performed by Galbraith Laboratories(Knoxville, Tenn.). H NMR spectra were obtained on a Varian 250 MHzspectrophotometer using chloroform-d₁ as a solvent and tetramethylsilane(TMS) as an internal reference.

EXAMPLE 1 Solution Polymerization of Sebacic Acid Using Phosgene orDiphosgene as the Coupling Agent

A solution of 1 eq. diacid and 2.5 to 3 eq. base in an organic solventwas prepared. Either PVP or K₂ CO₃ was added as an insoluble acidacceptor. The resulting insoluble solid, PVP.HCl or KCl, respectively,was removed by filtration. The filtrate was added dropwise to asufficient volume of petroleum ether to precipitate the polymer out ofsolution. The precipitated polymer was then isolated by filtration anddried in a vacuum oven for 24 hours at 40° C.

The results of the polymerization of sebacic acid, as a model, usingeither phosgene or diphosgene as coupling agents with various acidacceptors are shown in Table I. The poly(sebacic anhydride) has a weightaverage molecular weight up to 16,300. The results are similar for the(SA) using either phosgene or diphosgene. All of the p(SA) formed hasthe same melting point and IR absorbance characteristics of anhydridebonds. Insoluble polyamines, poly(4-vinylpyridine) (PVP), as well assoluble amines, TEA, pyridine, and TMEDA were used. The polymers formedwith these reagents have similar molecular weights, indicating a similarrole for the different amine bases as acid acceptors. Using aheterogeneous acid acceptor, PVP, does not affect the polymerization, asshown in Table I.

A non-amine heterogeneous base, K₂ CO₃, yields a lower molecular weightpolymer. This may be due to the formation of a soluble intermediatecomplex of acid-amine which increases the interaction with the couplingagent under homogeneous conditions. Although the PVP is insoluble in thereaction medium, it swells and forms a similar acid-PVP complex. K₂ CO₃,however, forms a heterogeneous mixture with the acid and thus reactsslower with the coupling agents to form the polymer.

                                      TABLE I                                     __________________________________________________________________________    Polymerization of Sebacic Acid Using Phosgene and Diphosgene as Coupling      Agents..sup.a                                                                 Coupling   Acid  Molecular Weight                                                                       IR    MP                                            Agent      Acceptor                                                                            Mw   Mn  (cm.sup.-1)                                                                         (°C.)                                  __________________________________________________________________________    1.  Phosgene Sol.                                                                        TEA.sup.b                                                                           14800                                                                              6250                                                                              1800                                                                             1740                                                                             75-77                                         2.  Phosgene Sol.                                                                        pyridine.sup.b                                                                      13700                                                                              5950                                                                              1800                                                                             1735                                                                             76-78                                         3.  Phosgene Sol.                                                                        TMEDA.sup.b                                                                         16300                                                                              6600                                                                              1805                                                                             1735                                                                             76-78                                         4.  Phosgene Sol.                                                                        PVP   13950                                                                              5350                                                                              1805                                                                             1735                                                                             80-81                                         5.  Phosgene Gas                                                                         Pyridine.sup.b                                                                      14100                                                                              6820                                                                              1805                                                                             1735                                                                             75-77                                         6.  Phosgene Gas                                                                         PVP   13200                                                                              6150                                                                              1800                                                                             1735                                                                             79-80                                         7.  Diphosgene                                                                           TEA.sup.b                                                                           12250                                                                              5780                                                                              1805                                                                             1735                                                                             76-78                                         8.  Diphosgene                                                                           Pyridine.sup.b                                                                      14300                                                                              6100                                                                              1805                                                                             1740                                                                             75-78                                         9.  Diphosgene                                                                           PVP   10900                                                                              5300                                                                              1800                                                                             1735                                                                             79-80                                         10. Phosgene Sol.                                                                        K.sub.2 CO.sub.3                                                                     6200                                                                              2700                                                                              1800                                                                             1740                                                                             76-78                                         11. Diphosgene                                                                           K.sub.2 CO.sub.3                                                                     6900                                                                              3500                                                                              1800                                                                             1740                                                                             77-78                                         __________________________________________________________________________     .sup.a Polymerization in chloroform, at 25° C., for 3 hours.           .sup.b Molecular weight and IR spectra were taken of the crude polymer.       The IR spectra contained amineHCl absorbance peaks at 2900-2600 cm.sup.-1     GPC output contained an isolated peak attributed to the amineHCl salt. Mw     was determined for the polymer peak only. The melting point was determine     for the pure polymer.                                                    

EXAMPLE 2 Comparison of Solution Polymerization Using Soluble andInsoluble amines

A method similar to that of Example 1 was used to polymerize thedicarboxylic acids. However, when either triethylamine (TEA) or pyridinewas used as the acid acceptor, the polymerization reaction was quenchedin petroleum ether and the polyanhydride, not the acid acceptor,precipitated from solution. The precipitated polymer was redissolved inchloroform and washed rapidly with a cold solution of water at pH 6. Thechloroform solution was dried over MgSO₄ and the polymer re-precipitatedby the dropwise addition of petroleum ether.

Several solvents, toluene, DMF, DMSO, and dioxane, were tested using TEAas the acid acceptor. The precipitated solids were removed byfiltration. The filtrate was evaporated to dryness in vacuo at 25° C.The resulting solid was dissolved in chloroform, the polymerprecipitated out by slow addition into petroleum ether, the precipitatedpolymer isolated by filtration and washed with diethyl ether to removeany traces of phosgene or diphosgene. The composition, yield and meltingpoints of the products formed with the various monomers and solventmixtures are shown in Table II.

                                      TABLE II                                    __________________________________________________________________________    Solution Polymerization of Diacids in Various Solvents.                                      Analysis of      Yield.sup.c                                                                       mp.sup.b                                  Monomer.sup.f                                                                       Solvent  Solution.sup.a                                                                        Solid.sup.b                                                                            (%) (°C.)                              __________________________________________________________________________    1. SA Chloroform.sup.e                                                                       pSA/TEA.HCl                                                                           --       d                                             2.    Toluene.sup.e                                                                          pSA     pSA + TEA.HCl                                                                           20 78-79                                     3.    N,N'-Dimethyl-                                                                         pSA     TEA.HCl  100 80-81                                           formamide                                                               4.    Dimethylsulfoxide                                                                      --      --           --                                        5.    Pyridine pSA/TEA.HCl                                                                           --       d                                             6.    Dioxane  pSA/TEA.HCl                                                                           TEA.HCl  d   --                                        7. CPP                                                                              Chloroform                                                                             TEA.HCl pCPP     100 265                                       8. TPA                                                                              Chloroform                                                                             TEA.HCl pTPA     100 >300                                      __________________________________________________________________________     .sup.a The solvent was evaporated and the residue was analyzed.               .sup.b Analysis of the precipitated solid.                                    .sup.c Pure polymer.                                                          .sup.d Yield cannot be determined due to the presence of TEA.HCl.             .sup.e Polymerized using either diphosgene or sebacoyl chloride as            coupling agents.                                                              .sup.f SA is sebacic acid, CPP is 1,3bis(p-carboxyphenoxy)propane, TPA is     Terephthalic acid.                                                       

The use of a solvent system wherein the polymer is in one reaction phase(either as a precipitate or in solution), and the acidacceptor-hydrochloride acid complex is in a second phase, complementaryto the polymer, is an alternative to the use of an insoluble acidacceptor. Table II describes polymerization of SA in several solventswith TEA as an acid acceptor, Polyanhydrides were obtained in good yieldin toluene and in DMF. TEA in toluene or DMF is complementary to the useof PvP in chloroform. In both approaches, the p(SA) is soluble in thereaction media. The insoluble hydrochloric acid-acid acceptor complex,whether an insoluble amine, PVP.HCl, or TEA.HCl salt, is removed byfiltration, leaving a polymer of greater than 99.7% purity with no needfor further purification.

EXAMPLE 3 Solution Polymerization comparing an Acid Chloride as theCoupling Agent with Phosgene and Diphosgene as the Coupling Agent

Solution polymerization was performed as before, using either phosgene,diphosgene or an acid chloride as the coupling agent and an acidacceptor Reactions between sebacic acid (1 eq.) and sebacoyl chloride (1eq.) were performed in chloroform and toluene in the presence of eitherPVP (insoluble) or TEA (soluble).

In a typical polymerization, 0.5 g (0.5 eq.) diphosgene was addeddropwise into a stirring mixture of 2.02 g (1.0 eq.) sebacic acid and 3g (2.5 eq.) poly(4-vinylpyridine) in 20 ml chloroform. After 3 hours at25° C., the insoluble PVP.HCl was removed by filtration. The filtratewas quenched in 100 ml petroleum ether. The precipitated polymer wasisolated by filtration, washed with anhydrous diethyl ether and driedfor 24 hours at 40° C. in a vacuum oven.

A comparison of the purity of p(SA) synthesized using soluble andinsoluble amines, TEA and PVP, respectively, with diphosgene or sebacoylchloride as coupling agents, as shown in Table III, demonstrates thatwhen soluble base, TEA, was used as an acid acceptor, the polymercontains a significant amount of TEA.HCl salt. The ratio of the salt tothe polymer was 4:1 and 2:1 for the coupling agents diphosgene andsebacoyl chloride, respectively. When PVP, an insoluble acid acceptor,was used p(SA) of greater than 99.7% purity was obtained for bothcoupling agents.

PVP has another advantage besides high purity of the end product. It canbe regenerated by neutralization with a sodium bicarbonate solution.Recycled PVP has a similar activity to that of the original PVP as anacid acceptor and forms a polyanhydride identical to the originalpolyanhydrides.

                                      TABLE III                                   __________________________________________________________________________    Presence of Amine hydrochloride in Solution Polymerized pSA as a Function     of                                                                            the Acid Acceptor.                                                            Polymerization                                                                          Yield  TEA:PSA        mp   Elemental                                Method.sup.a                                                                            (%).sup.e                                                                         IR.sup.b                                                                         'H NMR.sup.c /Elemental                                                                  GPC.sup.d                                                                         (°C.)                                                                       (% N,                                                                             % Cl)                                __________________________________________________________________________      A       f   +  4.3:1/3.5:1                                                                              +   70-185.sup.g                                                                       7.21,                                                                             19.63                                  B       62  -  --         -   81-82                                                                              0.18,                                                                             <0.10                                  C       f   +  1.9:1/2.4:1                                                                              +   68-185.sup.g                                                                       5.26,                                                                             13.14                                  D       65  -  --         -   81-83                                                                              0.11,                                                                             0.027                                  E       60  -  --         -   81-83                                                                              0.11,                                                                             0.015                                __________________________________________________________________________     .sup.a A is TEA/diphosgene; B is PVP/diphosgene; C is TEA/sebacoyl            chloride; D is PVP/sebacoyl chloride, E is regenerated PVP/diphosgene.        .sup.b Typical absorbance of TEAHCL follows (film cast); 2740 (w), 2600       (s, broad), 2530 (w, sharp), 2500 (s, sharp) cm.sup.-1.                       .sup.c 'H NMR of TEAHCl (CDCl.sub.3): 3.11 (q, 2, J = 7.3 Hz), 1.42 (t, 3     J = 7.3 Hz); 'HNMR of PSA (CDCl.sub.3): 2.45 (t, 4, J = 7.3 Hz), 1.66 (br     t, 4, J = 7.3 Hz), 1.33 (br s, 8).                                            .sup.d Sharp peak at Rt = 12.3 min.                                           .sup.e Pure poly(sebacic anhydride)                                           .sup.f Yield cannot be determined due to the presence of TEA.HCl.             .sup.g m.p. of TEA.HCl is 261° C.                                 

Attempted purification of polymers synthesized with TEA as the acidacceptor using rapid water extraction results in a decrease in molecularweight and hydrolysis, as evidenced by GPC and IR spectra. The IRspectra of the polymer before and after purification reveals thedisappearance of the amine salt (2740-2500 cm⁻¹). The IR spectra ofpolyanhydrides prepared with PVP as an acid acceptor reveals pureunhydrolyzed polymer.

EXAMPLE 4 Solution Polymerization of an Insoluble Polyanhydride with asoluble Acid Acceptor

Insoluble polyanhydrides, poly(1,3-bis(p-carboxyphenoxy)propane) andpoly(terephthalic anhydride), were polymerized as above but using onlysoluble amines such as TEA or pyridine as the acid acceptors. Thepolymers precipitated during the reaction and were isolated byfiltration. The results are shown in Table IV.

                                      TABLE IV                                    __________________________________________________________________________    Solution Polymenzation of Insoluble Polymers Using Phosgene and               Diphosgene                                                                    as Coupling Agents.                                                                       Coupling                                                                           Acid  Molecular Weight                                                                       IR     MP                                     Acid.sup.c  Agent.sup.b                                                                        Acceptor.sup.c                                                                      Mw   Mn  (cm.sup.-1)                                                                          (°C.)                           __________________________________________________________________________    1. Adipic acid                                                                            P    TEA   7600 3350                                                                              1820                                                                              1735                                                                             70-73                                  2. "        P    PVP   8300 3600                                                                              1810                                                                              1740                                                                             70-74                                  3. "        D    TEA   6900 3200                                                                              1820                                                                              1740                                                                             69-73                                  4. Dodecanoic acid                                                                        P    TEA   14100                                                                              6500                                                                              1810                                                                              1740                                                                             92-95                                  5. "        P    PVP   12600                                                                              5900                                                                              1810                                                                              1740                                                                             90-95                                  6. "        D    PVP   13750                                                                              4800                                                                              1805                                                                              1740                                                                             92-94                                  7. Terephthalic acid.sup.a                                                                P    TEA   --   --  1780                                                                              1735                                                                             >300                                   8. "        P    Pyridine                                                                            --   --  1780                                                                              1735                                                                             >300                                   9. "        D    TEA   --   --  1780                                                                              1730                                                                             >300                                   10.                                                                              PDP      P    TEA   8400 3650                                                                              1800                                                                              1735                                                                              98-101                                   "        P    PVP   7950 2100                                                                              1805                                                                              1740                                                                             100-102                                   "        D    TEA   9200 2350                                                                              1805                                                                              1735                                                                              98-102                                   CPP.sup.a                                                                              P    TEA   --   --  1780                                                                              1730                                                                             262-265                                   "        P    TEA   --   --  1780                                                                              1735                                                                             265-266                                   "        D    TEA   --   --  1780                                                                              1735                                                                             264-266                                   PHE--GLU D    TEA   7500 2800                                                                              1800                                                                              1740                                                                             --                                        "        D    PVP   4680 2400                                                                              1800                                                                              1740                                                                             --                                     __________________________________________________________________________     .sup.a P is phosgene solution, D is diphosgene,                               .sup.b Polymers are insoluble.                                                .sup.c PDP is phenylenedipropionic acid, CPP is                               1,3bis(p-carboxyphenoxy)propane, GLU--PHE is                                  Ncarbobenzoxy-L-phenylalanyl-L-glutamic acid.                            

Isolation of the polymer using an insoluble acid acceptor is preferredover the two phase solvent separation method since high boiling pointsolvents such as DMF or toluene do not have to be removed at ambienttemperature to avoid decomposition of the formed polyanhydride. Incontrast to the traditional use of dehydration agents, the use ofinsoluble acid acceptors such as poly(4-vinylpyridine) or inorganicbases yield highly pure polymers. The use of various solvent systems iscomplementary to the use of the insoluble bases in chloroform. Thechoice of the right solvent system can be used to precipitateexclusively either the polymer or the amine-acid salt, using filtrationto yield pure polymers. These methods are advantageous for thepolymerization of heat sensitive dicarboxylic acids such astherapeutically active diacids and polyanhydrides of dipeptides.

EXAMPLE 5 Solution Polymerization of Polyanhydrides from Dipeptides ofAspartic or Glutamic Acid

Polyanhydrides formed of dipeptides of an amino acid and either glutamicacid or aspartic acid can be prepared using the present method. Forexample, as shown in FIG. 2, phenylalanine-Z-glutamic acid orphenylalanine-Z-aspartic acid can be prepared. Z represents a protectinggroup.

The starting material, N-carbobenzoxy-L-phenylalanyl-L-glutamic acid,for the synthesis of poly(N-carbobenzoxy-DL-phenylalanine glutamic)anhydride, was synthesized according to The Practice of PeptideSynthesis, Bodanszky, et al., Editors (Springer-Berlag, New York 1984).One gram monomer (2.5 mmol) was dissolved in a solution of 0.51 g TEA (5mmol) in 10 ml chloroform, followed by the slow addition of 1.25 mmoldiphosgene over 15 minutes. The resulting polyanhydride was isolated andpurified. The analysis is shown as part of in Table IV.

The present invention has been described with respect to specificembodiments. Variations and modifications of the method for synthesizingpolyanhydrides using a coupling agent and an insoluble acid acceptor ortwo phase solvent separation will be obvious to those skilled in thearts in the foregoing detailed description. Such modifications andvariations are intended to come within the scope of the appended claims.

We claim:
 1. A highly pure poly(amide-anhydride) produced by reacting insolution under dehydrative coupling conditions a coupling agent and aninsoluble acid acceptor with at least one dipeptide selected from thegroup consisting of dipeptides of aspartic acid, dipeptides of glutamicacid, and combinations thereof.
 2. The highly pure poly(amide-anhydride)of claim 1 wherein the coupling agent is selected from the groupconsisting of phosgene, diphosgene, and acid chlorides.
 3. The highlypure poly(amide-anhydride) of claim 1 wherein the insoluble acidacceptor is selected from the group consisting of insoluble polyamines,crosslinked polyamines, and inorganic bases.
 4. A highly purepoly(amide-anhydride) produced by reacting in solution a coupling agentwith a dipeptide selected from the group consisting of dipeptides ofaspartic acid, dipeptides of glutamic acid, and combinations thereof,wherein the polyanhydride is soluble in solution, substantiallyunhydrolized, and free of coupling agent and reaction byproducts.
 5. Amethod for polymerizing highly pure poly(amide-anhydride)s comprisingreacting in a non-aqueous solution under dehydrative conditions acoupling agent and an acid acceptor with at least one dipeptide of aminoacids selected from the group consisting of glutamic acid, asparticacid, and combinations thereof, wherein the acid acceptor is insolublein a solvent in which the poly(amide-anhydride) is soluble.
 6. Themethod of claim 5 wherein the coupling agent is selected from the groupconsisting of phosgene, diphosgene, and acid chlorides.
 7. The method ofclaim 5 wherein the insoluble acid acceptor is selected from the groupconsisting of insoluble polyamines, crosslinked polyamines, andinorganic bases.